Signal transduction enzymes such as protein kinases and phosphatases play pivotal roles in mediating cellular responses to a wide variety of stimuli. These enzymes are often targeted to specific substrates or cellular compartments through their interaction with cellular "anchoring proteins" (Hubbard and Cohen, Trends Biochem. Sci. 18:172-177, 1993). This anchoring or compartmentalization is thought to be critical in determining the specificity of response for a particular stimulus (Scott and Carr, News Physiol. Sci. 7:143-148, 1992; Rubin, Biochim. Biophys. Acta 1224:467-479, 1994; Mochly-Rosen, Science 268:247-251, 1995). Anchoring of cyclic AMP (cAMP)-dependent protein kinase (PKA or A-kinase) is accomplished by the binding of the regulatory subunit (R) to an amphipathic helix-binding motif located within A-kinase anchoring proteins (AKAPs) (Carr et al., J. Biol. Chem. 266:14188-14192, 1991).
Synthetic peptides containing an amphipathic helix domain are able to competitively disrupt PKA binding to AKAPs (Carr et al., J. Biol. Chem. 267:13376-13382, 1992). Microinjection of these anchoring inhibitor peptides (AIPs) into neurons or skeletal muscle cells disrupts PKA anchoring and PKA modulation of glutamate receptor channels (Rosenmund et al., Nature 368:853-856, 1994) and voltage-gated calcium channels (Johnson et al., Proc. Natl. Acad. Sci. USA 91:11492-11496, 1994). However, microinjection is impractical for normal pharmaceutical applications.